Investigational Dengue Vax Has Gaps

Analysis suggests it's more effective in older children.

Action Points

An experimental vaccine was effective in reducing dengue disease in children but benefits of reduced hospitalization during follow-up were largely seen in children 9 years of age or older.

Although the age difference in vaccine efficacy and safety is unexplained, there are plausible biologic hypotheses but a chance finding cannot be ruled out.

A tetravalent vaccine against dengue fever was safe and efficacious over a long-term follow-up, researchers reported.

Pooled data from 2 Phase III trials and a Phase IIb study showed a reduction in dengue disease among children who got the vaccine, according to Melanie Saville, MBBS, of Sanofi Pasteur in Lyons, France, and colleagues.

But the safety analysis was complicated, they noted, because the vaccine appeared to be less safe for children under 9 than for those 9 or older, with relative risks of dengue admission of 1.58 and 0.50, respectively.

The difference will need careful monitoring, Saville and colleagues concluded.

While the age difference is unexplained, they argued, "several interrelated plausible biologic hypotheses" might shed some light.

Among them:

The first wild-type dengue infection is typically less severe than a second; the vaccination process might have mimicked a first infection in children with no previous exposure to the virus, so that later exposure led to more severe disease and hospital admission.

Age itself might have played a role, since younger children would be expected to have a less developed immune system.

It is possible that the finding is a result of chance, commented Cameron Simmons, PhD, of the University of Melbourne in Australia.

"Potentially," Simmons added, "booster doses of vaccine might be used to break the disease-risk profile."

The vaccine, dubbed CYD-TDV, is the most advanced candidate and could be registered and reviewed by the World Health Organization in 2016, Simmons noted.

In the trials, the vaccine was given three times -- at baseline, and at 6 months and 12 months -- and participants were followed for efficacy and safety for another 13 months after the final dose, Saville and colleagues noted.

To assess long-term safety, the researchers analyzed data from more than 33,000 children, 2 through 16 years, who took part in the trials in Asian-Pacific and Latin American countries. The primary endpoint of the analysis is hospital admission for virologically confirmed dengue.

That endpoint was chosen as a surrogate outcome for severe disease, as the investigators sought to show that the immune response to vaccination did not lead to a predisposition to severe disease and that the risk of severe disease did not rise over time as antibody levels fell.

The long-term study is intended to cover the 4 years after the end of the initial 25-month efficacy analyses; the current report offers interim safety data for the year three, Saville and colleagues reported.

All told, the investigators had data on 33,266 of the 35,146 participants in the trials, including 22,177 in the vaccine groups and 11,089 in the control groups.

Based on pooled results, the relative risk for hospital admission for dengue was 0.84 (with a 95% confidence interval from 0.56 to 1.24) among all participants, the researchers found.

But the relative risk was 1.58 (with a 95% confidence interval from 0.83 to 3.02) among those under 9 and 0.50 (with a 95% confidence interval from 0.29 to 0.86) among those 9 and older, they reported.

The difference was paralleled by the pooled rates of efficacy for symptomatic dengue during the first 25 months -- 60.3% for all participants, compared with 65.6% for those 9 and older and 44.6% among those younger than 9, Saville and colleagues reported.

All participants admitted to hospital for dengue had a full recovery, the researchers said.

The trials, Simmons wrote, "have been superbly conducted and are hugely informative; they have delivered major insights into disease burden, clinical epidemiology, and immunity."

A key insight is that "partial, waning immunity is a particularly unwelcome outcome after vaccination," he wrote, concluding that the "bumpy road to a vaccine-based solution for dengue continues."

The study was supported by Sanofi Pasteur. Saville and several other authors are employees of the company.

Simmons disclosed relationships with Sanofi Pasteur, Merck, and GlaxoSmithKline. He also reported he is a member of a group seeking to use modified mosquitoes to control dengue virus transmission, which could be seen as a technology in competition with dengue vaccines.

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